1. Field of the Invention
The present invention relates to a pharmaceutical composition for preventing or treating diseases associated with beta-amyloid accumulation containing morpholin or piperazine based compounds having SO3H or COOH as an active ingredient.
2. Description of the Related Art
As the global average life span of people increases and we see a transition to an aging society in which the population of elderly increases, the incidence rate of neurodegenerative diseases such as senile dementia represented by Alzheimer's disease, cerebral apoplexy, or Parkinson's disease has been greatly increased.
Dementia comprehensively include complex clinical symptoms from which a normally developed brain is impaired or destroyed by external factors such as trauma or diseases to abnormal cognitive impairments such as language, learning, intelligence, and etc. and higher mental functions, and progressive memory disorders bring disorders in social-vocational functions, accompanied by behavioral disorders such as aphasia, agnosia, apraxia, etc. Dementia may be largely divided into dementia by Alzheimer's disease, vascular dementia, dementia by specific neural diseases and systemic diseases, etc., and the dementia by Alzheimer's disease is responsible for 50% or more of them.
One of the anatomical characteristics of Alzheimer's disease is degeneration and death of nerve cells responsible for memory and cognition. One of the pathological characteristics is finding of neurofibrillary tangles within nerve cells and senile plaques outside nerve cells. Beta-amyloid deposits are discovered in the senile plaques, and it is usually known that they are in the form of fibril with a β-sheet structure, which is formed from beta-amyloid monomers. It is known that Alzheimer's disease is caused by various factor factors such as immunological factors, genetic factors, viral infection, toxic materials, damages, and etc. According to what has been known, it is reported that destruction of nerve cells by neurotoxicity of neural plaques produced from accumulation of beta-amyloid proteins in the brain and neurodegeneration by nerve fiber bundles produced from accumulation of hyperphosphorylated tau proteins in the brain are major causes of Alzheimer's dementia.
The beta-amyloid described above is a protein found in a patient with Alzheimer's disease, and a polypeptide consisting of 39-43 amino acid residues derived from amyloid protein precursor (APP) (Seubert, P., C. Vigo-Pelfrey, et al. (1992). “Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids.” Nature 359(6393): 325-7., Shoji, M., T. E. Golde, et al. (1992). “Production of the Alzheimer amyloid beta protein by normal proteolytic processing.” Science 258(5079):126-9., Busciglio, J., D. H. Gabuzda, et al. (1993). “Generation of beta-amyloid in the secretory pathway in neuronal and normeuronal cells.” Proc Natl Acad Sci USA 90(5):2092-6). Amyloid protein precursor (APP) is degraded into beta-amyloid 40 or 42 (Aβ40 or Aβ42) monomer by β-secretase and γ-secretase, and then accumulated to form oligomers. The accumulation of these oligomers leads to a step of forming fibril. A strong neurotoxicity is exhibited in the brain from the state when the beta-amyloid in various steps becomes oligomers, leading to death of neuronal cells (Walsh, D. M., I. Klyubin, et al. (2002). “Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.” Nature 416(6880):535-9., Stine, W. B., Jr., K. N. Dahlgren, et al. (2003). “In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.” J Biol Chem 278(13):11612-22., Ferreira, S. T., M. N. Vieira, et al. (2007). “Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases.” IUBMB Life 59(4-5):332-45). Therefore, it is important to disaggregate the accumulated beta-amyloid or inhibit the accumulation of beta-amyloid for treatment of Alzheimer's disease.
The isoforms of beta-amyloid constituting most of the accumulated amyloids are beta-amyloids 40 and 42 consisting of 40 and 42 amino acids (Bitan, G., M. D. Kirkitadze, et al. (2003). “Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways.” Proc Natl Acad Sci USA 100(1):330-5), and glycosaminoglycan (GAG) and proteoglycan (PG) are materials which aid in the accumulation of the beta-amyloid among various factors involved in the accumulation of the amyloid. Glucosaminoglycan/proteoglycan present in cell membranes are combined with beta-amyloid and structurally changed to aid in the accumulation of beta-amyloid. In particular, the sulfate moieties portions of glucosaminoglycan/proteoglycan were reported to combine with the HHQK region corresponding to the 13rd-16th portion of 40 or 42 amino acids of beta-amyloid to serve as an important factor in the accumulation.
From the idea that a material called acetylcholine is decreased in the brains of patients with Alzheimer's disease when compared with normal subjects, there are drugs to be developed in the direction of increasing the quantity of acetylcholine in the brain or increasing the activity of cholinergic neurons as therapeutic agents currently developed. However, because commercially available drugs of these series such as donepezil, rivastigmin, galantamin, memantine, and etc. do not treat the disease fundamentally but rather improve cognitive functions, it is necessary to improve the agents to overcome their side effects and limitations.
Thus, the present inventors have performed research to develop therapeutic agents inhibiting the accumulation of beta-amyloid, found that morpholine or piperazine based compounds containing a sulfuric or carboxylic acid structures may inhibit the accumulation of beta-amyloid fibrils or oligomers, degrade the accumulated beta-amyloid fibrils and oligomers to inhibit the toxicity by beta-amyloid, and be useful as pharmaceutical compounds for prevention or treatment of diseases associated with beta-amyloid accumulation, for dementia including Alzheimer's disease, Down's syndrome, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloid disease, Dutch-type amyloidosis, and inclusion body myositis (IBM), and made the present invention.